Background: Ischemia reperfusion injury (IRI) is mediated by a complex cascade of pro-inflammatory and oxidative processes. We have reported that signal regulatory inhibitory protein (SIRP)-α is expressed by renal tubular epithelial cells (rTEC). We have also shown that the stress-response protein thrombospondin-1 (TSP1) is increased following renal IRI and binds to SIRPα. However, it is unclear how TSP1-SIRPα signaling contributes to the pathophysiology of IRI.

Methods: Age-matched male wild-type (WT) mice, and SIRPα mutant mice (SIRPα^mut, lacking the cytoplasmic recruitment domains) underwent bilateral renal IRI and were assessed for renal function and biomolecular analysis. WT and SIRPα^mut rTEC were studied in vitro. As SIRPα is expressed by rTEC and non-parenchymal cells, chimeric mice were generated to explore the contribution of differing cell compartments to IRI; mice were irradiated and rescued with WT or SIRPα^mut bone marrow.

Results: IRI resulted in significantly elevated serum creatinine in WT mice, which was mitigated in SIRPα^mut animals (2.3±0.4 in WT versus 0.98±0.4 mg/dl in SIRPα^mut, p<0.01). Changes in renal function reflected improvements in SIRPα^mut histologic findings, inflammatory infiltrate (Ly6G⁺neutrophils and F4/80⁺macrophages) and levels of pro-inflammatory cytokines (IL-1ß, TNFα, IL-6). TSP1 was expressed to a similar degree post-IRI regardless of genetic background. Measurement of reactive oxygen species (ROS) by cytochrome c assay in whole kidney demonstrated a 2-fold increase in superoxide anion in WT mice post-IRI (p<0.001) but not in SIRPα^mut mice, compared to sham-operated controls. Expression of oxidative protein modification 3-nitrotyrosine was reduced in SIRPα^mut mice compared to WT, although total renal expression of NADPH oxidase 1, 2 and 4 were unchanged. WT rTEC displayed 3-fold upregulated ROS in response to exogenous TSP1 (p<0.01), which did not occur in SIRPα^mut cells. SIRPα^mut mice, regardless of hematopoietic reconstitution, were fully protected against renal dysfunction and ROS generation following IRI.

Conclusion: These data provide evidence for a role for SIRPα promoting renal IRI through generation of pathologic ROS, and blockade of SIRPα may provide a novel therapeutic target to modify IR-mediated damage.

CITATION INFORMATION: Rogers N, Meijles D, Pagano P, Isenberg J. Signal Inhibitory Regulatory Protein-α Regulates Pathologic Reactive Oxygen Species in Acute Kidney Injury. Am J Transplant. 2017;17 (suppl 3).

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